7pqk
From Proteopedia
(Difference between revisions)
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[7pqk]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7PQK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7PQK FirstGlance]. <br> | <table><tr><td colspan='2'>[[7pqk]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7PQK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7PQK FirstGlance]. <br> | ||
- | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=81D:(S)-3-(Aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1,2]oxaborol-1(3H)-ol'>81D</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.15Å</td></tr> |
+ | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=81D:(S)-3-(Aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1,2]oxaborol-1(3H)-ol'>81D</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7pqk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7pqk OCA], [https://pdbe.org/7pqk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7pqk RCSB], [https://www.ebi.ac.uk/pdbsum/7pqk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7pqk ProSAT]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7pqk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7pqk OCA], [https://pdbe.org/7pqk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7pqk RCSB], [https://www.ebi.ac.uk/pdbsum/7pqk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7pqk ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/SYL_MYCTU SYL_MYCTU] | [https://www.uniprot.org/uniprot/SYL_MYCTU SYL_MYCTU] | ||
- | <div style="background-color:#fffaf0;"> | ||
- | == Publication Abstract from PubMed == | ||
- | Prodrugs have little or no pharmacological activity and are converted to active drugs in the body by enzymes, metabolic reactions, or through human-controlled actions. However, prodrugs promoting their chemical bioconversion without any of these processes have not been reported before. Here, we present an enzyme-independent prodrug activation mechanism by boron-based compounds (benzoxaboroles) targeting leucyl-tRNA synthetase (LeuRS), including an antibiotic that recently has completed phase II clinical trials to cure tuberculosis. We combine nuclear magnetic resonance spectroscopy and X-ray crystallography with isothermal titration calorimetry to show that these benzoxaboroles do not bind directly to their drug target LeuRS, instead they are prodrugs that activate their bioconversion by forming a highly specific and reversible LeuRS inhibition adduct with ATP, AMP, or the terminal adenosine of the tRNA(Leu). We demonstrate how the oxaborole group of the prodrugs cyclizes with the adenosine ribose at physiological concentrations to form the active molecule. This bioconversion mechanism explains the remarkably good druglike properties of benzoxaboroles showing efficacy against radically different human pathogens and fully explains the mechanism of action of these compounds. Thus, this adenosine-dependent activation mechanism represents a novel concept in prodrug chemistry that can be applied to improve the solubility, permeability and metabolic stability of challenging drugs. | ||
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- | Adenosine-Dependent Activation Mechanism of Prodrugs Targeting an Aminoacyl-tRNA Synthetase.,Hoffmann G, Le Gorrec M, Mestdach E, Cusack S, Salmon L, Jensen MR, Palencia A J Am Chem Soc. 2023 Jan 4. doi: 10.1021/jacs.2c04808. PMID:36599057<ref>PMID:36599057</ref> | ||
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- | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
- | </div> | ||
- | <div class="pdbe-citations 7pqk" style="background-color:#fffaf0;"></div> | ||
- | == References == | ||
- | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> |
Current revision
Co-Crystal Structure of M. tuberculosis LeuRS in Complex with the Adduct Formed by Prodrug Cmpd1 with Adenosine-monophosphate
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